tbuckley/cabot-search huggingface dataset:
EPEN-06. Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
Authors: Michael Bockmayr, Kim Harnisch, Lara Pohl, Leonille Schweizer, Theresa Mohme, Meik Körner, Malik Alawi, Abigail Suwala, Mario Dorostkar, Camelia Monoranu, Martin Hasselblatt, Annika Wefers, David Capper, Jürgen Hench, Stephan Frank, Timothy Richardson, Ivy Tran, Elisa Liu, Matija Snuderl, Lara Engertsberger, Martin Benesch, Andreas von Deimling, Denise Obrecht, Martin Mynarek, Stefan Rutkowski, Markus Glatzel, Julia Neumann, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients’ clinical course are unknown. We assembled a cohort of 185 tumors classified as MPE based on DNA methylation from pediatric, adolescent, and adult patients. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPEB, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. Tumors in the methylation class MPE were histologically diagnosed as WHO grade I (59%), WHO grade II (37%), or WHO grade III tumors (4%). 75/77 analyzed tumors expressed HOXB13, which is a diagnostic feature not detected in other spinal ependymal tumors. Based on DNA methylation, our series split into two subtypes. MPE-A occurred in younger patients (median age 27 vs. 45 years, p=7.3e-05). They were enriched with WHO grade I tumors and associated with papillary morphology and MGMT promoter hypermethylation (all p&amp;lt;0.001). MPE-B included most tumors initially diagnosed as WHO grade II and cases with tanycytic morphology. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. 15/30 MPE-A could not be totally resected compared to 1/58 MPE-B (p=6.3e-08), and progression-free survival was significantly better for MPE-B (p=3.4e-06, 10-year relapse rate 33% vs. 85%). We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
QOL-20. Post-Intensive-Care Syndrome – pediatric (PICS-p) among patients with brain tumors – therapeutic strategies and preventive recommendations
Authors: Justyna Korzeniewska
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Patients with brain tumors needed in intensive care unit (ICU) stay due to tumors symptoms or neurosurgery, experience a complex of physical, psychological, and cognitive symptoms. This constellation of signs and symptoms has been named Post-Intensive-Care Syndrome – pediatric (PICS-p). An interesting problem emerging from this research and requires a deeper exploration are the differences between PICS-p symptoms and primary tumors effects or side effects of treatment e.g. irradiation. METHOD: Psychological repeated testing and long-term observation was performed in 350 childhood brain tumor survivors (various types and localizations of tumor) to determine PICS-p symptoms. Age at psychological diagnosis ranged from 6 to 20 years. Full psychological outcome included assessment of psychophysical, cognitive and affective problems. The patients were examined using battery of neuropsychological methods and psychological interview. Analysis of medical history was also performed. The next level of the study was distinguished between PICS-p symptoms and the effects of tumor localization and oncology treatment, including radiotherapy. RESULTS: In our sample patients presents low scores in the all PICS-p domains: physical, cognitive and mental. Low level of motor skills, impairing daily living activities are characteristic. In this group lower IQ scores, poorer visual motor integration, learning disabilities, memory and language problems persisted. Typical problems in mental area are depressive symptoms, anxiety with intrusive memories, emotional and behavioural disruptions, socialization problems with significantly low level of social contacts. CONCLUSIONS: The results of this study suggest that PICS-p well describes and explains the psychosocial problems of these patients. It allows prepare an individual psychological interventions and rehabilitative program for particular patient as well as therapeutic strategies for whole group of patients. Draft recommendations for diagnosis of PICS-p specific for patients with brain tumors, risk factors and preventive procedures will be presented and discussed.
Role of chemokine systems in cancer and inflammatory diseases
Authors: Hongyi Li, Min Wu, Xia Zhao
Journal: MedComm (2022)

Abstract Chemokines are a large family of small secreted proteins that have fundamental roles in organ development, normal physiology, and immune responses upon binding to their corresponding receptors. The primary functions of chemokines are to coordinate and recruit immune cells to and from tissues and to participate in regulating interactions between immune cells. In addition to the generally recognized antimicrobial immunity, the chemokine/chemokine receptor axis also exerts a tumorigenic function in many different cancer models and is involved in the formation of immunosuppressive and protective tumor microenvironment (TME), making them potential prognostic markers for various hematologic and solid tumors. In fact, apart from its vital role in tumors, almost all inflammatory diseases involve chemokines and their receptors in one way or another. Modulating the expression of chemokines and/or their corresponding receptors on tumor cells or immune cells provides the basis for the exploitation of new drugs for clinical evaluation in the treatment of related diseases. Here, we summarize recent advances of chemokine systems in protumor and antitumor immune responses and discuss the prevailing understanding of how the chemokine system operates in inflammatory diseases. In this review, we also emphatically highlight the complexity of the chemokine system and explore its potential to guide the treatment of cancer and inflammatory diseases.
Gefitinib plus chemotherapy versus gefitinib alone in untreated patients with <i>EGFR</i>-mutated non–small cell lung cancer and brain metastases (GAP Brain): An open-label, randomized, multicenter, phase 3 study.
Authors: Likun Chen, Xue Hou, Meichen Li, Guowu Wu, Weineng Feng, Jin Su, Honghua Jiang, Guanming Jiang, Baishen Zhang, Jing Chen, Zhixuan You
Journal: Journal of Clinical Oncology (2022)

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P &lt; 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P &lt; 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.
Capturing uveal melanoma (UM) global practice patterns and clinical outcomes in the collaborative ocular melanoma natural history (OMNi) study (NCT04588662).
Authors: Joseph J. Sacco, Marlana M. Orloff, Sapna Pradyuman Patel, Max Conway, Li-Anne Lim, Lotte S. Fog, David Sia, John McKenzie, Daniel McKay, Roderick O'day, Timothy Isaacs, Alexander Noor Shoushtari, Ryan J. Sullivan, Sarah Kin, Femida Hussein Gwadry-Sridhar, Anthony M. Joshua, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2022)

TPS9610 Background: Geographical differences in the management of primary UM, surveillance for recurrence, and care of metastatic disease have emerged based upon local expertise, treatment availability and insurance coverage. We have initiated accrual to OMNi (NCT04588662), an ambispective database developed to provide contemporary real-world data of UM, capturing its natural history and serving as a virtual biospecimen repository. The overall objectives of OMNi are to characterize regional/international UM management practice patterns and associated clinical outcomes in an effort to inform best practice recommendations. Methods: OMNi utilizes the Pulse Infoframe Healthie platform, a globally compliant platform which enables the structured collection of data mapped to Observational Medical Outcomes Partnership. The data fields created permit longitudinal capture of data including baseline patient and tumor characteristics, treatment of primary lesion and outcomes, surveillance patterns, time to disease recurrence, treatment of recurrent disease with outcomes, and survival. Inclusion criteria include a diagnosis of uveal melanoma and the ability to provide written informed consent for participation in the prospective registry or an institutional waiver by the IRB/ethics committee for retrospective data collection without written informed consent. We have initiated data collection at 3 US and 3 Australian centers, with 184 patients enrolled to date. Based upon feasibility assessment, we anticipate retrospective data entry for ̃2,000 patients and annual recruitment of ̃700 patients once all centers are active. Data collected in this OMNi collaboration, which will include additional US, UK and Australian sites, will facilitate new insights, hypothesis testing, as well as clinical trial development and conduct, and through a governance structure, will be made accessible for research. The OMNi dataset can serve and aid in interpretation of clinical trial outcomes in the real-world, facilitate cutting-edge research, and accelerate the development of diagnostics and therapeutics. Clinical trial information: NCT04588662.
CD38 Mediates Lung Fibrosis by Promoting Alveolar Epithelial Cell Aging
Authors: Huachun Cui, Na Xie, Sami Banerjee, Tapan Dey, Rui-Ming Liu, Veena B. Antony, Yan Y. Sanders, Taylor S. Adams, Jose L. Gomez, Victor J. Thannickal, Naftali Kaminski, Gang Liu
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

A prevailing paradigm recognizes idiopathic pulmonary fibrosis (IPF) originating from various alveolar epithelial cell (AEC) injuries, and there is a growing appreciation of AEC aging as a key driver of the pathogenesis. Despite this progress, it is incompletely understood what main factor(s) contribute to the worsened alveolar epithelial aging in lung fibrosis. It remains a challenge how to dampen AEC aging and thereby mitigate the disease progression.
Age at presentation of infertile men has stably increased over the last two decades: Analysis from a longitudinal study
Authors: L. Boeri, P. Capogrosso, G. Fallara, F. Belladelli, E. Pozzi, M. Raffo, C. Corsini, L. Candela, D. Cignoli, N. Schifano, A. D'Arma, E. Ventimiglia, P. Luca, E. Papaleo, V. Mirone, F. Montorsi, A. Salonia
Journal: European Urology (2022)
Safety and Glycemic Outcomes With a Tubeless Automated Insulin Delivery System in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Clinical Trial
Authors: Jennifer L. Sherr, Bruce W. Bode, Gregory P. Forlenza, Lori M. Laffel, Melissa J. Schoelwer, Bruce A. Buckingham, Amy B. Criego, Daniel J. DeSalvo, Sarah A. MacLeish, David W. Hansen, Trang T. Ly, Jennifer L. Sherr, Kate Weyman, Eileen Tichy, Michelle VanName, Michelle Brei, Melinda Zgorski, Amy Steffen, Lori Carria, Bruce W. Bode, Anna Busby, Gregory P. Forlenza, R. Paul Wadwa, Robert Slover, Erin Cobry, Laurel Messer, Lori M. Laffel, Elvira Isganaitis, Louise Ambler-Osborn, Emily Freiner, Christine Turcotte, Lisa Volkening, Melissa Schoelwer, Sue A. Brown, Katie Krauthause, Emma Emory, Mary Oliveri, Bruce A. Buckingham, Laya Ekhlaspour, Ryan Kingman, Amy B. Criego, Betsy L. Schwartz, Laura M. Gandrud, Aimee Grieme, Jamie Hyatt, Daniel J. DeSalvo, Siripoom McKay, Kylie DeLaO, Carolina Villegas, Sarah A. MacLeish, Jamie R. Wood, Beth A. Kaminski, Terri Casey, Wendy Campbell, Kim Behm, Ramon Adams, David W. Hansen, Sheri L. Stone, Suzan Bzdick, Jane Bulger, Lynn Agostini, Sarah Doolittle, Kaisa Kivilaid, Krista Kleve, Trang T. Ly, Bonnie Dumais, Todd Vienneau, Lauren M. Huyett, Joon Bok Lee, Jason O’Connor, Eric Benjamin
Journal: Diabetes Care (2022)

Very young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population.A total of 80 children aged 2.0-5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy.There were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70-180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204).Use of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.
Trabectedin and hypofractionated radiation for high-risk, localized, and metastatic soft tissue sarcoma: A retrospective study.
Authors: Narine Wandrey, Ryan Michael Lanning, Camille Stewart, Anthony D. Elias, Martin McCarter, Breelyn A. Wilky
Journal: Journal of Clinical Oncology (2022)

11564 Background: Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with high unmet need. Trabectedin (T) is an FDA-approved chemotherapy that blocks cell cycling and DNA repair pathways. Combination T and conventional radiation (XRT) in STS nonrandomized phase 1/2 trials demonstrated objective response rates (ORR) of 36-72% in localized and low burden metastatic disease, while pre-treated metastatic STS treated with T alone has an ORR of 10-14%. We hypothesize that the combination of T and hypofractionated radiation (hXRT) will exhibit a tolerable safety profile and improve ORR relative to historical outcomes with T or hXRT alone. Here we report our experience in the treatment of oligometastatic STS with combined T and hXRT. Methods: We reviewed our institutional experience to identify patients treated with T and XRT. We included patients with high risk localized or metastatic STS (majority of patients had metastatic disease at time of treatment). All patients received at least 1 cycle of T and concurrent XRT to at least 1 lesion. ORR and local control rate (LCR) were determined for irradiated lesions by RECIST 1.1. Results: Between 2020 – 2021, 9 STS patients with 21 tumors were treated at the University of Colorado with XRT and concurrent T. The median age was 39.2 (range 26.0 – 64.6) years. 8 patients had metastatic disease at the time of treatment. Treated tumor sites included 1 lung,1 extremity, 2 liver, 2 retroperitoneal, 5 bone, and 10 peritoneal. The following histologic subtypes were included: myxoid liposarcoma (3), uterine leiomyosarcoma (2), non-uterine leiomyosarcoma (1), dedifferentiated liposarcoma (1), undifferentiated pleomorphic sarcoma (1), and synovial sarcoma (1). All metastatic patients were pre-treated with a median of 3 lines of systemic therapy. The median number of T cycles delivered was 5 (range 1 – 20). The median XRT prescription dose was 3000cGy (range 2000cGy – 5000cGy), with 8 patients having received hXRT (5 -10 fractions) and 1 having received conventionally fractionated XRT. 8 patients underwent 1 course of XRT, while 1 received 3 courses in combination with T. All patients had a Karnofsky performance status equal to or greater than 60. After a median follow-up 5.4 months, the LCR of treated lesions was 90.5%. The ORR (CR or PR) was 57.1% and median decrease in tumor diameter at time of maximum response was 52.0%. The median time until maximum response was 3.7 months. 2 patients experienced grade 3 toxicity (LFT elevation) attributable to T, and 2 patients experienced grade 3 toxicity due to XRT. There were no grade 4 or 5 toxicities. Conclusions: T in combination with hXRT appears to be safe and feasible in this patient population. Based on these data, a phase 1/2 prospective clinical trial is being planned in oligometastatic and high risk localized STS. [Table: see text]
Peripheral blood mononuclear cells (PBMCs), an ideal liquid biopsy approach to evaluate systematic immunity and predict response of neoadjuvant chemo-immunotherapy in resectable NSCLC.
Authors: Lei Zhang, Likun Hou, Junqi Wu, Chongwu Li, Tao Hu, Changbin Zhu, Chunyan Wu, Chang Chen
Journal: Journal of Clinical Oncology (2022)

e20618 Background: Immune checkpoint inhibitors (ICIs) dramatically improved clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC). However, ICIs are not the scenario of “One-size fits to all”. It is of great importance to explore biomarkers, especially via liquid biopsy-based approach, to predict or monitor treatment response. Besides comprehensive genomic profiling of primary tumor tissue, this study focused on gene expression profile of PBMCs at baseline as well as one week post 1 st immunotherapy administration, and its association with major pathological response (MPR) of neoadjuvant chem-immunotherapy in resectable NSCLC patients. Methods: Pre-treatment tumor biopsies and PBMC at baseline (D0) and 7 days after neoadjuvant chem-immunotherapy (D7) were collected from 27 patients with stage IB-IIIB NSCLC from two prospective clinical trials (NCT04422392 and NCT04762030) between Aug 2019 and July 2021. Tumor biopsies were subjected for comprehensive genomic profiling by an NGS panel covering 571 cancer related genes, and RNA from PBMC was subjected to an RNA sequencing panel covering transcripts of 2660 genes. (Amoy Diagnostics, Xiamen, China). Single sample gene set enrichment analysis (ssGSEA) was used to assess enrichment of inflammatory-related gene sets. CIBERSORT and in-housed established DAISM-DNN algorithm were applied to estimate immune cell populations from PBMC-derived gene expression profile. Results: Patients received chemo-immunotherapy achieved 59.3% of MPR. Stronger signatures including effector T cell and IFN-γ/Effector T-cell were significantly enriched in baseline PBMC samples in MPR patients (p = 0.028, p = 0.042 respectively). In parallel, significant increasing Naïve CD8 positive T cells was observed in PBMC at D7 in MPR patients by both CIBERSORT (p = 0.047) and DAISM-DNN algorithm (p = 0.018). Interestingly, at D7, signature of M0 macrophage was enriched in PBMC from patients with non-MPR. In addition, comprehensive genomic profiling indicated a numerically higher level of tumor mutation burden (TMB) in pretreatment tumor samples in MPR patients (Median TMB, MPR 11.51 mut/Mb vs Non-MPR 7.19 mut/Mb, p = 0.074). Conclusions: Expression profile of baseline PBMC as well as dynamics of PBMC profile in a short period (7 days) may predict the clinical efficacy of neoadjuvant chemo-immunotherapy. More patients are being enrolled into this study. Moreover, to validate these findings, large-scale and prospective investigations are warranted. Clinical trial information: NCT04422392 and NCT04762030.